HDL, the "good" cholesterol, can be bad for your heart, Cleveland Clinic research shows

Dr. Stanley Hazen, cardiologist and vice chair of research at Cleveland Clinic's Lerner Research Institute, and his research group have shown that good cholesterol, or HDL, can go bad and actually cause damage in the artery wall, leading to heart disease.

(Cleveland Clinic )

CLEVELAND, Ohio-- HDL, long known as "good" cholesterol for its tendency to help prevent the buildup of artery-clogging plaque, has a Jekyll and Hyde tendency to turn bad and cause damage that can lead to heart disease, according to research from the Cleveland Clinic published online today.

This dysfunctional HDL not only no longer does its normal job of clearing plaques, it actually makes them worse by causing inflammation in the vessel walls, and may help explain the conundrum of why drug treatments that boost HDL levels have thus far failed to improve heart disease outcomes.

Clinic researchers described how HDL goes bad in their paper, published in Nature Medicine, and are close to commercial release of a blood test that will allow doctors to detect the dysfunctional form of the cholesterol carrier in the blood.

"It's not only a new diagnostic test but it's also a potentially new target for the treatment of heart disease, because the dysfunctional HDL is an active pro-inflammatory player now that we see in the disease process," said Dr. Stanley Hazen, cardiologist and vice chair of translational research at the Clinic's Lerner Research Institute and senior author on the report.

Dr. Michael Lauer, director of the division of Cardiovascular Sciences at the National Heart Lung and Blood Institute, said Hazen's research should help provide an important piece of the puzzle that will help explain the HDL conundrum.

"Almost without exception every effort we've made to raise HDL has failed," Lauer said, pointing to a recent failed trial of niacin to raise HDL called AIM-HIGH. "It's very strange, and in many respects it doesn't make much sense."

Hazen's study "provides really solid evidence that there are different kinds of HDL, and some of them are harmful," he said, which could explain the discrepancy.

The study also indicates that efforts to improve heart disease by targeting HDL right now are unlikely to be successful and shouldn't be part of routine care, Lauer said.

HDL, or high density lipoprotein, is a bit like a car, Hazen said, whose job is to ferry passengers—molecules of cholesterol—away from the vessel walls and other parts of the body to the liver for removal. LDL, or low density lipoprotein, has the opposite job: It carries cholesterol molecules to the vessel wall, where they are used by cells for important things like constructing cell walls and making hormones.

In the dysfunctional HDL, however, the “car” is damaged. It may still be carrying plenty of passengers, or cholesterol molecules, but it’s either moving very slowly and doesn’t make it to its destination or gets turned around and takes the passengers the wrong way.

Hazen’s research shows that in people with heart disease, about 1 in 5 HDL particles in the artery wall -- where the particle’s function is to remove cholesterol-- is dysfunctional. People who have more of this dysfunctional HDL are at higher risk of heart disease, independent of traditional risk factors such as age, diabetes, smoking, and blood pressure.

Traditional HDL cholesterol tests don’t pick up the dysfunctional HDL because they only show the amount of cholesterol, or “number of passengers” each HDL particle is carrying, not the state or function of the HDL itself, Hazen said.

“It’s actually the function of the HDL particle that’s more important than the amount of cholesterol it’s carrying,” he said. “If [the HDL’s] function changes it doesn’t matter how many people are sitting in the car. If it’s no longer moving 50 miles per hour and is only moving one mile per hour, you can have twice the cargo sitting in cars like that but sitting in a traffic jam.”

Complicating efforts to detect the dysfunctional HDL is its scarcity in the blood—while the modified form is relatively common in the artery wall, it accounts for only 1 in 14,000 HDL particles in the circulation of people with heart disease.

The Clinic group's blood test to detect the bad HDL, which has been licensed to spin-off company Cleveland HeartLab, may be commercially available as soon as the end of the year.

“We think that this will help us to identify, even in people who have a really high HDL cholesterol, who is really protected and who isn’t,” Hazen said.

In 2004, Hazen and the Lerner Research group identified the enzyme, myeloperoxidase, or MPO, which is responsible for turning HDL bad. MPO, which is expressed in white blood cells as a normal part of the immune system, is found in high quantities in the plaques that build up in artery walls.

Their discovery led to a test for detecting MPO, also licensed by Cleveland HeartLab, which can be used to detect heart disease risk.

"What that suggests is that we shouldn't be going after the HDL, but the MPO," Lauer said. "Only time will tell, but it will be very interesting to see if [agents that target MPO] will work."

Interestingly, one of HDL’s other functions is to soak up excess MPO from the blood.

“We think that HDL has evolved to not only carry cholesterol but also to bind or sequester MPO to keep it from doing bad things in the artery wall,” Hazen said.

Hazen believes their work will continue to reveal and unravel how startlingly complex the HDL and heart disease connection is.

"I think that's true of everything we do in medicine and biology—everything turns out to be so much more complicated than we thought it was," Lauer said of Hazen's team's discoveries. "But that's what makes it so much fun."